Studies on the clinical pharmacology of biochemically specific antidepressants produce both therapeutic advances and increased knowledge concerning the biological basis for affective illness. Further investigations of pharmacokinetic variance have shown that renal clearance is a major determinant in the elimination of active hydroxy metabolites of tricyclic antidepressants and may explain altered drug response in the elderly. In vitro and in vivo animal and human studies are elucidating the extent to which active hydroxy metabolites are important and the mechanisms which determine their concentrations. Identifying the pharmacodynamics (effect produced by known concentration) of selected antidepressants has advanced in several areas: (1) demonstration of increased functional norepinephrine combined with decreased total production following desipramine; (2) finding a possible dopaminergic effect of desipramine indexed by increased prolactin; (3) questioning whether a serotonergic effect of zimelidine accounts for increased vasopressin, not found after other drugs; (4) discovering an unexpected commmon reduction of total NE production after both drugs; (5) using sufficiently low doses of clorgyline to selectively inhibit MAO-A in man has provided a powerful new treatment for previously unresponsive bipolar rapid cyclers. This latter finding may provide a therapeutic break through.